p53 gene is a typical tumor suppressor gene which has been reported to be frequently mutated in human cancers. p53 protein is known to be capable of suppressing onset and progress of cancer by acting as a transcription factor to transcriptionally activate target genes. More specifically, it is believed that when a mutation occurs in the genes of a normal cell and it starts to become tumorigenesis, p53 protein arrests the cell cycle at the G1 anaphase and performs DNA repair during that time, or when repair is impossible it destroys the incipient cancerous cells by apoptosis (Kotsu Igaku 53 (5/6), 178-180, 1999).
DR5 (Death Receptor 5) is known as one protein whose transcription is induced by p53 protein and which is involved in p53-dependent apoptosis. DR5 induces apoptosis by binding a tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). DR4, DcR1, and DcR2 are also known as TRAIL receptors. DcR1 and DcR2 have TRAIL-binding regions but lack active intracellular death regions and therefore do not induce apoptosis. On the other hand, DR4 and DR5 include both TRAIL-binding regions and intercellular death regions, and they induce apoptosis through these intercellular death regions (Science 277, 815-818 (1997)). TRAIL exhibits selective toxicity for cancer cells over normal cells both in vitro and in vivo (J. Biol. Chem. 271, 12687-12690). This is attributed to the fact that DcRs of TRAIL receptor genes are expressed more dominantly in normal cells than in cancer cells.
Siah-1 (seven in absentia homologue-1) is known as another protein whose transcription is induced by p53 (EMBO J. 17, 2736-2747 (1998)). Siah-1 is activated by p53 protein to cause apoptosis and cell cycle arrest.
More specifically, the protease complex proteasome is involved in Siah-1-induced apoptosis and cell cycle arrest. The proteasome is an enzyme which recognizes ubiquitin in a ubiquitinated target protein and degrades the target protein. When Siah-1 binds to an enzyme part of which binds ubiquitin to a target protein, it activates the ubiquitin-binding enzyme and consequently promotes degradation of the target protein by the proteasome. One target protein of the proteasome is the β-catenin protein, and degradation of β-catenin protein induces suppression of Cyclin D1, Myc and other genes expression, resulting in apoptosis and cell cycle arrest. (Genes Dev. 11, 2701-2714 (1997), Genes Dev. 12, 1775-1780 (1998), Mol. Cell 7, 915-926 (2001)).
As described above, because activation of DR5 gene and Siah-1 gene at the transcription level induces apoptosis and cell cycle arrest, they play an important role in tumor suppression, and if substances could be found which activated transcription of these genes they would be extremely useful for cancer therapy.